CANOMAD and other chronic ataxic neuropathies with disialosyl antibodies (CANDA).

INTRODUCTION: CANOMAD/CANDA are syndromes characterized by ataxic neuropathy, ophthalmoplegia, monoclonal gammopathy, cold agglutinins and disialosyl antibodies. METHODS: A retrospective review of our neuromuscular autoantibody panel database was performed. Anti-GD1b seropositive patients with ataxia were included. RESULTS: Eleven patients were identified. Median age at onset was 56 years. Median disease duration was 6 years. All patients had gait disorders. Nine had ocular motility abnormalities. Most had a monoclonal protein and all had elevated serum IgM. Electrodiagnostic studies showed a mixed axonal/demyelinating pattern (6), an axonal pattern (4), or a pure demyelinating pattern (1). Ultrasounds showed nerve enlargement patterns consistent with acquired demyelination. A nerve biopsy showed near complete loss of myelinated axons with preservation of smaller axons. Rituximab was the most effective immunotherapy. CONCLUSION: CANOMAD/CANDA are rare and debilitating disorders with characteristic clinical and diagnostic findings. In our cohort, nerve ultrasound showed regional nerve enlargement and rituximab was the most effective immunomodulatory therapy.

Diagnosis and management of adult hereditary cardio-neuromuscular disorders: A model for the multidisciplinary care of complex genetic disorders.

Genetic disorders that disrupt the structure and function of the cardiovascular system and the peripheral nervous system are common enough to be encountered in routine cardiovascular practice. Although often these patients are diagnosed in childhood and come to the cardiologist fully characterized, some patients with hereditary neuromuscular disease may not manifest until adulthood and will present initially to the adult cardiologist for an evaluation of an abnormal ECG, unexplained syncope, LV hypertrophy, and or a dilated cardiomyopathy of unknown cause. Cardiologists are often ill-equipped to manage these patients due to lack of training and exposure as well as the complete absence of practice guidelines to aid in the diagnosis and management of these disorders. Here, we review three key neuromuscular diseases that affect the cardiovascular system in adults (myotonic dystrophy type 1, Friedreich ataxia, and Emery-Dreifuss muscular dystrophy), with an emphasis on their clinical presentation, genetic and molecular pathogenesis, and recent important research on medical and interventional treatments. We also advocate the development of interdisciplinary cardio-neuromuscular clinics to optimize the care for these patients.

Multifocal radiculoneuropathy during ipilimumab treatment of melanoma.

INTRODUCTION: Ipilimumab, a monoclonal anti-CTLA-4 antibody, is used to treat melanoma. Neuromuscular side effects, possibly autoimmune, may occur. METHODS: In this investigation we undertook a retrospective review of patient records. RESULTS: After 3 doses of ipilimumab, a 31-year-old man developed asymmetric, severe weakness involving all limbs, respiration, and cranial nerves, which was progressive over 2 weeks. EMG/NCS showed an axonal polyradiculoneuropathy with multifocal motor conduction blocks. CSF protein was 749 mg/dl. Nerve pathology showed inflammation around the endoneurial microvessels and subperineurial edema and inflammation. Spine MRI showed leptomeningeal and anterior and posterior root enhancement. Strength improved slowly over months after ipilimumab discontinuation and immunomodulating treatment. CONCLUSIONS: Ipilimumab toxicity presented as a monophasic, multifocal, asymmetric polyradiculoneuropathy involving roots and peripheral and cranial nerves. Ipilimumab may produce a polyradiculoneuropathy with disruption of the blood-nerve barrier due to a microvasculopathy.

Coenzyme Q10 deficiency in children: frequent type 2C muscle fibers with normal morphology.

INTRODUCTION: Neurological disorders with low tissue coenzyme Q10 (CoQ10) levels are important to identify, as they may be treatable. METHODS: We evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders. We compared 18 with CoQ10 deficiency in muscle to 31 with normal CoQ10 values. RESULTS: Muscle from CoQ10-deficient patients averaged 5.5-fold more frequent type 2C muscle fibers than controls (P < 0.0001). A type 2C fiber frequency of ≥ 5% had 89% sensitivity and 84% specificity for CoQ10 deficiency in this cohort. No biopsy showed active myopathy. There were no differences between groups in frequencies of mitochondrial myopathologic, clinical, or laboratory features. Multiple abnormalities in muscle oxidative enzyme activities were more frequent in CoQ10-deficient patients than in controls. CONCLUSIONS: When a childhood mitochondrial disorder is suspected, an increased frequency of type 2C fibers in morphologically normal muscle suggests CoQ10 deficiency.

Clinical and laboratory features of neuropathies with serum IgM binding to TS-HDS.

INTRODUCTION: In this investigation we studied clinical and laboratory features of polyneuropathies in patients with serum IgM binding to the trisulfated disaccharide IdoA2S-GlcNS-6S (TS-HDS). METHODS: We retrospectively compared 58 patients with selective IgM binding to TS-HDS to 41 consecutive patients with polyneuropathies without TS-HDS binding. RESULTS: Patients with IgM vs. TS-HDS commonly had distal, sensory, axonal neuropathies. Weakness was associated with IgM M-proteins. Hand pain and serum IgM M-proteins were more common than in control neuropathy patients. TS-HDS antibody binding was often selectively κ class. Biopsies showed capillary pathology with thickened basal lamina and C5b9 complement deposition. IgM in sera with TS-HDS antibodies often bound to capillaries. CONCLUSIONS: Serum IgM binding to TS-HDS is associated with painful, sensory > motor, polyneuropathies with an increased frequency of persistent hand discomfort, serum IgM M-proteins, and capillary pathology. Serum IgM binding to TS-HDS suggests a possible immune etiology underlying some otherwise idiopathic sensory polyneuropathies.

Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.

OBJECTIVE: To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles. METHODS: Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6. RESULTS: Exome analysis in 3 affected individuals from a family with dominant LGMD and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself. INTERPRETATION: Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.

Eosinophilic vasculitis in an isolated central nervous system distribution.

Eosinophilic vasculitis has been described as part of the Churg-Strauss syndrome, but affects the central nervous system (CNS) in <10% of cases. A 39-year-old woman with a history of migraine without aura presented to an institution in an acute confusional state with concurrent headache and left-sided weakness. Laboratory evaluation showed an increased cerebrospinal fluid (CSF) protein level, but otherwise unremarkable serologies. Magnetic resonance imaging showed bifrontal polar gyral-enhancing brain lesions. Her symptoms resolved over two weeks without residual deficits. Eighteen months later the patient presented with similar symptoms and neuroradiological findings showed involvement of territories different from those in her first episode. Brain biopsy showed transmural, predominantly eosinophilic, inflammatory infiltrates and fibrinoid necrosis without granulomas. She improved when treated with corticosteroids. To our knowledge, this is the first case of non-granulomatous eosinophilic vasculitis isolated to the CNS. No aetiology for this patient's primary CNS eosinophilic vasculitis has yet been identified.

Eosinophilic vasculitis in an isolated central nervous system distribution.

BACKGROUND: Eosinophilic vasculitis has been described as part of the Churg-Strauss syndrome, but affects the central nervous system (CNS) in <10% of cases; presentation in an isolated CNS distribution is rare. We present a case of eosinophilic vasculitis isolated to the CNS. CASE REPORT: A 39-year-old woman with a history of migraine without aura presented to an institution (located in the borough of Queens, New York, USA; no academic affiliation) in an acute confusional state with concurrent headache and left-sided weakness and numbness. Laboratory evaluation showed increased cerebrospinal fluid (CSF) protein level, but an otherwise unremarkable serological investigation. Magnetic resonance imaging showed bifrontal polar gyral-enhancing brain lesions. Her symptoms resolved over 2 weeks without residual deficit. After 18 months, later the patient presented with similar symptoms and neuroradiological findings involving territories different from those in her first episode. Again, the CSF protein level was high. She had a raised C reactive protein level and erythrocyte sedimentation rate. Brain biopsy showed transmural, predominantly eosinophilic, inflammatory infiltrates of medium-sized leptomeningeal arteries without granulomas. She improved, without recurrence, when treated with a prolonged course of corticosteroids. CONCLUSIONS: To our knowledge, this is the first case of non-granulomatous eosinophilic vasculitis isolated to the CNS. No aetiology for this patient's primary CNS eosinophilic vasculitis has yet been identified. Spontaneous resolution and recurrence of her syndrome is an unusual feature of the typical CNS vasculitis and may suggest an environmental epitope with immune reaction as the cause.

Acute hepatic failure caused by an acute aortic dissection with cardiac tamponade: a case report.

An acute cardiac tamponade from any cause may result in rapid deterioration of hepatic function in a previously healthy patient. We describe a case of an acute ascending aortic dissection that presented as acute hepatic failure, due to an acute cardiac tamponade and severe right heart failure. The differential diagnosis of the aetiology of acute liver failure is extensive and includes poisonings, vascular obstruction and sepsis, particularly on the background of decompensated liver disease. Many of these conditions are associated with hypotension. The acute presentation in our patient, combined with the lack of a characteristic history delayed the diagnosis of a proximal (type A) dissection with tamponade and subsequent hepatic failure. Severe right-sided heart failure as a result of conditions such as cardiac tamponade should be excluded in patients presenting with acute hepatic failure of unknown aetiology.

An fMRI investigation of emotional engagement in moral judgment.

The long-standing rationalist tradition in moral psychology emphasizes the role of reason in moral judgment. A more recent trend places increased emphasis on emotion. Although both reason and emotion are likely to play important roles in moral judgment, relatively little is known about their neural correlates, the nature of their interaction, and the factors that modulate their respective behavioral influences in the context of moral judgment. In two functional magnetic resonance imaging (fMRI) studies using moral dilemmas as probes, we apply the methods of cognitive neuroscience to the study of moral judgment. We argue that moral dilemmas vary systematically in the extent to which they engage emotional processing and that these variations in emotional engagement influence moral judgment. These results may shed light on some puzzling patterns in moral judgment observed by contemporary philosophers.

Stress-induced failure of osmoregulation in the parasitic nematode Pseudoterranova decipiens: indirect evidence for hormonal regulation.

When third-stage larvae of Pseudoterranova decipiens maintained at 5 degrees C are placed in either 40% artificial sea water (ASW, iso-osmotic) or 15% ASW (hypo-osmotic) and weighed once at 0 h and again at 24 h, they neither lose nor gain weight, and the osmotic pressure (OP) of their pseudocoelomic fluid (PCF) remains unchanged. In contrast, when worms are weighed six additional times during the 24 h interval, those maintained in isoosmotic conditions lose weight, while those maintained in hypo-osmotic conditions gain weight. Worms which had been exposed to hypo-osmotic conditions and weighed at various times between 0 and 24 h exhibited an increase in weight which was correlated with the number of weighings. Worms exposed to hypo-osmotic conditions and weighed three additional times between 0 and 24 h also gained weight, and the OP of the PCF decreased such that worms experiencing the greatest increase in weight suffered the greatest dilution of the PCF. In worms ligatured at the head or tail or at the head and tail, and then exposed to either 15% or 40% ASW, the effect of multiple weighings is exaggerated in a complex way. The presence of a ligature on the tail in worms immersed in an iso-osmotic medium leads to an increase in weight and to a very marked additional increase in weight in worms immersed in a hypo-osmotic medium. The presence of a head ligature in worms in an iso-osmotic medium leads to a decrease in weight and to a smaller weight gain in a hypo-osmotic medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Osmoregulation in the parasitic nematode Pseudoterranova decipiens.

When subjected to hyper- or hypo-osmotic stress at 5 degrees C for 24 h, third-stage larvae of the parasitic nematode Pseudoterranova decipiens do not exhibit changes in mass or in the osmotic pressure of the pseudocoelomic fluid. Immersion in solutions containing 3H2O demonstrates that exchange with the water in the pseudocoelomic fluid is substantially complete within 24 h. Sacs composed of cylinders of body wall without the intestine and pseudocoelomic fluid do not gain weight when immersed for 24 h in hypotonic medium. Metabolic poisons abolish the ability of whole worms and sacs to maintain their weight when immersed in hypotonic media. These observations support the conclusion that the nematode is capable of at least short-term osmoregulation and that the site of osmoregulation is the body wall. The observations that more fluid is passed from the anus in some hypo-osmotically stressed worms and that worms ligatured at the tail exhibit a small increase in mass when exposed to hypo-osmotic conditions may indicate that the intestine plays a minor and subsidiary role in osmoregulation.

Water compartments and osmoregulation in the parasitic nematode Pseudoterranova decipiens.

A study of the time course of penetration of 3H2O into whole worms suggests that worms immersed in a hypo-osmotic environment (15% artificial sea water) reach full exchange equilibrium more slowly than worms in an iso-osmotic environment (40% artificial sea water). The apparent water content, determined by dry mass, matches that determined by 3H2O exchange when worms are immersed for 24 h in 40% artificial sea water (ASW), but the water content measured by 3H2O exchange is lower when worms are kept in a hypo-osmotic environment for 24 h. These differences disappear after 48 h. No such differences are apparent when sacs, consisting of cylinders of body wall lacking their intestines and pseudocoelomic fluid and closed at both ends by ligatures, are immersed in either 40% or 15% ASW for 24 h. The placing of ligatures at the head, but not at the tail, results in a failure of worms immersed in 40% ASW or 15% ASW containing 3H2O to achieve full exchange equilibrium within 24 h. These results suggest that although worms immersed in an iso-osmotic environment drink, those immersed in a hypo-osmotic environment do not, a conclusion supported by studies involving the addition of [14C]inulin to the medium. The application of ligatures to the head and tail of worms immersed in 40% ASW results in a slower penetration of 3H2O into the pseudocoelomic fluid, whereas similar ligatures do not further retard the penetration in worms exposed to 15% ASW. The results are consistent with a model which sees the pseudocoelomic fluid as consisting of two compartments containing water, one of which exchanges more slowly than the other.